1,5-diazacyclononanes

ABSTRACT

SUBSTITUTED 1,5-DIAZACYCLONONES ARE PREPARED BY TREATING SUBSTITUTED 1,5-DIAZABICYCLO(4.3.0) NONANES WITH SODIUM IN THE PRESENCE OF LIQUID AMMONIA AND ARE USEFUL AS CENTRAL NERVOUS SYSTEM STIMULANTS AND ANTIDEPRESSANTS.

United States Patent Oflice 3,663,536 1,5-DIAZACYCLONONANES William J.Houlihan, Mountain Lakes, N.J., assignor to Sandoz-Wander, Inc.,Hanover, NJ. N Drawing. Original application July 21, 1966 ,Ser. No.566,751, now Patent No. 3,497,513, dated Feb. 24, 1970. Divided and thisapplication Nov. 13, 1969,'Ser.

Int. Cl. C07d 53/00 US. Cl. 260-239 BC 4 Claims ABSTRACT OF THEDISCLOSURE Substituted 1,5-diazacyclononanes are prepared by treatingsubstituted 1,5-diazabicyclo[4.3.0]nonanes with sodium in the presenceof liquid ammonia and are useful as central nervous system stimulantsand antidepressants.

wherein:

R represents hydrogen; or lower alkoxy, preferably containing from 1 to4 carbon atoms; e.g., methoxy, ethoxy, propoxy and butoxy; and

R represents straight chain lower alkyl, preferably containing from 1 to4 carbon atoms, e.g., methyl, ethyl, propyl and butyl.

The above compounds may be prepared by reacting 3- benzoylpropionic acidor an appropriately substituted derivative thereof with3-hydrozinopropanol to form the corresponding 2-(3-hydroxypropyl) 6phenyl-4,5-dihydropyridazin(2H)-3-one. The latter is then eitherconverted (via halide synthesis) to the corresponding 2-(3-chloropropyl) 6 phenyl-4,S-dihydroxypridazin(2H)-3- one or reduced toform the corresponding 1-(3-hydroxypropyl)-3-phenyl-hexahydropyridazine.Either of the compounds thus obtained is then converted to thecorresponding 9-pheny1-1,5-diazabicyclo [4.3.0]nonane which in turn3,663,536 Patented May 16, 1972 is reacted with an alkyl halide to formthe N -(lower alkyl) halide salt thereof. The latter is then convertedto the desired 1,5-diazacyclononane by treatment with sodium and liquidammonia.

The above process may be illustrated structurally as follows:

lHalide (RX) 7 E 5 ll? Reduction Step 2 (CH2)3C1 In the above formulae Rand R are as defined except that with respect to Formulas II, III, IV, Vand VI, R additionally can be chloro, and X represents halogen having anatomic weight of at least 35, i.e., chloro bromo or iodo.

As illustrated above, Step 1 of the process involves the reaction of a3-benzoylpropionic acid with S-hydrazinopropanol to form thecorresponding 2-(3-hydroxypropyl)-6-phenyl-4,S-dihydropyridazin(2H)-3-0ne (II). This reaction isconveniently carried out in the presence of an inert organic solvent andat elevated temperatures. However, neither the solvent nor temperatureemployed is critical. Suitable solvents include benzene, toluene, xyleneand chlorobenzene. Preferably, the reaction is carried out at refluxtemperature to facilitate continuous removal of water. To facilitate theformation of water, the reaction may be carried out in the presence of acatalytic amount of hydrogen ions such as by the use of an arylsulfonicacid, e.g., benzenesulfonic acid, p-toluenesulfonic acid and the like.The resulting product (II) can be readily isolated employingconventional techniques.

The reduction (Step 2) of the pyridazinone (II) or (IV) to thecorresponding pyridazine (III) or diazabicyclononane (V), respectively,is readily carried out employing a hydride reducing agent, preferably analuminum hydride, such as lithium aluminum hydride, butyl aluminumhydride, triisobutyl aluminum hydride and the like. The reduction isconveniently eflected in the presence of an inert organic solvent and atan elevated temperature, preferably reflux temperature. Suitablesolvents include the ethers, such as diethyl ether and the like, andmixtures of ethers and benzene or toluene. However, neither the solventnor temperature employed is critical. The resulting products (III) or(V) are readily recovered in conventional manner.

Step 3 of the process involves the conversion of the 2-(3-hydroxypropyl)-pyridazinone (H) to the corresponding2-(3-chloropropyl)-pyridazinone (IV). This is accomplished in standardmanner employing any of the conventional agents used for this purpose.The preferred agent, however, is thionyl chloride. The reaction isconveniently carried out in any suitable inert organic solvent, such as,for example, benzene, hexane, dichloromethane, chloroform and carbontetrachloride. It is preferred to carry out the reaction at refluxtemperature, but it can be carried out at room temperature (20 C.) ifdesired. The re sulting product (IV) can be readily recovered inconventional manner.

The conversion of the pyridazine (III) to the correspondingdiazabicyclononane (V), as indicated by Step 4 of the above reactionscheme is elfected employing the same conditions as set forth for Step3. This reaction provides via halide synthesis and spontaneous ringclosure the diazabicyclononane (V). 5

Steps 5 and 6 of the process involve the introduction of the alkylsubstituent (R') into the ring system followed by the opening of thenitrogen-nitrogen bond in the ring. In Step 5 the diazabicyclononane (V)is reacted with an appropriate halide to form the corresponding N (R')halide salt thereof (VI). This reaction is conveniently carried out inthe presence of a suitable inert organic solvent, such as, for example,diethyl ether, pentane, hexane, benzene, toluene, xylene,dichloromethane and chloroform. It is preferred to carry out thereaction at room temperature or below although elevated temperatures upto reflux temperature can be employed if desired. The resulting halidesalt (VI), which is readily isolated employing conventional techniques,is then converted to the desired corresponding 1,5-diazacyclononane (I)by reacting the halide salt (VI) with sodium in the presence of liquidammonia (Step 6). The reaction is conveniently carried out atatmospheric pressure and at a temperature at which ammonia is a liquid,i.e., below 30 C. Preferably, the reaction is carried out at thetemperature afforded by a Dry Ice-acetone bath (-86 C.). In carrying outthe reaction a solvent is not necessary since an excess of liquidammonia can be used for this purpose. It should be noted that theformation of the diazacyclononane via the reaction of the halide salt(VI) with sodium and liquid 4 ammonia is indeed unusual. The resultingdiazacyclonname (1) is readily recovered in conventional manner.

With respect to the last step of the process (Step 6) it will beappreciated that when the halide salt (VI) contains a chloro substituentattached to the benzene ring, the subsequent treatment thereof withsodium and liquid ammonia will also serve to remove such chlorosubstituent thereby yielding the corresponding9-pheny1-1,5-diazacyclononane.

With respect to the various steps of the process discussed above, it ispossible that the solvent employed therein can be dispensed with if anyof the reactants employed are liquids at the temperature at which thereaction is conducted. In such instances an excess of such reactant canbe used in lieu of the solvent.

Various of the propionic acids employed in Step 1 of the process areknown and can be prepared as described in the literature. Such otherswhich are not specifically disclosed in the literature may be readilyprepared from available materials by methods analogous to thosedescribed in the literature for the preparation of the known compounds.

All of the compounds of structural Formulas I, III, V and VI haveasymetric centers and therefore exist as optically active isomers.Separation and recovery of the respective isomers may be readilyaccomplished employing conventional techniques and such isomers areincluded within the scope of this invention.

The end compounds of the present invention in their free base form(compounds of Formula I) are useful because they possess pharmacologicalactivity. In particular, such compounds are central nervous systemstimulants and can be used as anti-depressants. Such compounds are alsouseful as hypotensives and local anesthetics. The intermediate compoundsof Fomiula V (in their free base form) are also useful as analgesics andcentral nervous system stimulants (anti-depressants).

For the above uses, the compounds may be combined with apharmaceutically acceptable carrier, and such other conventionaladjuvants, as may be necessary, and administered orally in such forms astablets, capsules, elixirs, suspensions or solutions, or parenterally insuch forms as injectable solutions, suspensions or emulsions.Furthermore, the compounds may be similarly administered in the form oftheir non-toxic pharmaceutically acceptable acid addition salts. Suchsalts possess the same order of act vity as the free base, are readilyprepared in conventional manner by reacting the base with theappropriate acid and accordingly are included within the scope of theinvention. Representative of such salts are the mineral acid salts suchas the hydrochloride, hydrobromide, sulfate, phosphate and the like andthe organic acid salts such as the succinate, benzoate, acetate,maleate, ptoluenesulfonate, benzenesulfonate and the like.

is noted above, the compounds of Formula I and V exist as opticalisomers. In some cases greater pharmacological activity or otherbeneficial attribute may be found with respect to a particular isomer,and in such instances administration of such isomer may be preferred.

For the above mentioned uses, the dosage administered will, of course,vary depending on the compound employed, the therapy desired and mode ofadministration. However, in general, satisfactory results are obtainedwith compounds of 'Formula I when administered at a daily dosage of fromabout 10 milligrams to about milligrams, preferably given in divideddoses of from about 2.5 milligram to about 75 milligrams throughout theday or In sustained release form. Statisfactory results are achievedwith compounds of Formula V when administered at a daily dosage of fromabout 50 milligrams to about 500 milligrams, preferably given in divideddoses of from about 12.5 milligrams to about 250 milligrams throughoutthe day or in sustained release form.

Representative formulations suitable for oral administration are tabletsprepared by standard tabletting techniques and containing the following:

Ingredient: Parts by wt. S methyl 9 phenyl 1,5 diazacyclononane (or acidaddition salt thereof) or 9- (p-chlorophenyl)- 1,5diazabicyclo[4.3.0]nonane (or acid addition salt thereof) 1 50Tragacanth 2 Lactose 39.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5

v 1 Calculated as the free base.

EXAMPLE 1 9- (p-methoxyphenyl) -1,5-diazabicyclo [4.3 .0] nonane Step A:Preparation of2-(3-hydroxypropyl)-6-(pmethoxyphenyl)-4,5-dihydropyridazin(2I-I)-3-one.-Toa flask equipped with a condenser, Dean-Stark tube and stirrer is added20.8 g. (0.10 mole) of 3-p-methoxybenzoylpropionic acid, 13.5 g. (0.15mole) of 3-hydrazinopropanol and 250 ml. of toluene. The mixture isstirred and refluxed until water ceases to separate in the Dean- Starktube. The solvent is then removed in vacuo on a rotary evaporator toyield an oil which solidified on standing. The resulting solid materialis crystallized from chloroform-pentane to obtain2-(3-hydroxypropyl)-6-(pmethoxyphenyl)-4,5-dihydropyridazin (2H)-3-one,M.P.

flask are stirred and refluxed for 80 hours and then cooled in an icebath. To the cooled mixture is then added dropwise 28.6 ml. of 2 Nsodium hydroxide and 42.9 ml. of water. The resulting mixture is thenfiltered, and the filtrate'concentrated on a rotary evaporator to obtain1-(3-hydroxypropyl)-3-(p-methoxyphenyl)-hexahydropyridazine as a viscousoil.

Step C: Preparation of 9-(p-methoxyphenyl)-l,5-diazabicyclo[4.3.0]nonane.-To a flask equippedwith a stirrer, condenser and dropping funnel is added 50.0 g. (0.20mole) of hexahydropyridazine and 500 ml. of dry chloroform. Whilestirring the mixture at room temperature, 21.3 ml. (0.3 mole) of thionylchloride is added and the resulting mixture refluxed overnight. Thechloroform solution 1- 3-hydroxypropyl) -3- (p-methoxyphenyl) is thenwashed first with 10% aqueous sodium bicarbonate solution until the washis alkaline and then with saturated aqueous sodium chloride solution,and the combined washings extracted twice with chloroform. The combinedchloroform layers are then dried with sodium sulfate, filtered and thefiltrate evaporated in vacuo on a rotary evaporator to yield crude9-(p-methoxyphenyl)- 1,5-diazabicyclo[4.3.0]nonane, B.P. -l52 C./ 6.5mm.

EXAMPLE 2 9-(-p-chlorophenyl)-1,5 -di-azabicyclo[4.3.0] nonane Step A:Preparation of 2-(3-hydroxypropyl)-6-(p-chlorophenyl)4,5-dihydropyridazin(2H)-3-one.To a flask equipped with a condenser,Dean-Stark tube and stirrer is added 63.9 g. (0.30 mole) of3-p-chlorobenzoylpropionic acid, 31.5 g. (0.35 mole) of3-hydrazinopropanol and 500 ml. of toluene. The mixture is stirred andrefluxed until water ceases to separate in the Dean-Stark tube. Thesolvent is then removed in vacuo on a rotary evaporator to yield an oilwhich solidifies on standing. The resulting solid material iscrystallized from chloroform-pentane to obtain2-(3-hydroxypropyl)-6-(p-chlorophenyl)-4,5-dihydropyridazin(2H)-3-one,M.P. 128-l32 C.

Step B: Preparation of l-(3-hydroxypropyl)-3-(p-chlorophenyl)hexahydropyridazine.To a flask equipped with a stirrer, condenser, gasinlet tube and Soxhlet tube containing 53.4 g. (0.20 mole) of2-(3-hydroxypropyl)- 6 (p-chlorophenyl) 4,5-dihydropyridazin(2H)-3-oneis added under nitrogen atmosphere 14.3 g. (0.376 mole) of lithiumaluminum hydride and 1500 ml. of absolute diethyl ether. The contents ofthe flask are stirred and refluxed for 80 hours and then cooled in anice bath. To the cooled mixture is then added dropwise 28.6 ml. of 2 Nsodium hydroxide and 42.9 ml. of water. The resulting mixture is thenfiltered, and the filtrate concentrated on a rotary evaporator to obtain1 (3-hydroxypropyl)-3-(pchlorophenyl)-hexahydropyridazine as a viscousoil. The latter solidifies on standing to yield product, M.P. 65 67 C.

Step C: Preparation of 9-(p-chlorophenyl)-l,5-diazabicyclo[4.3.0]nonane.-To a flask equipped witha stirrer, condenser and dropping funnel is added 18.0 g. (0.07 mole) of1 (3-hydroxypropyl)-3-(p-chlorophenyD-hexahydropyridazine and 200 ml. ofdry chloroform. While stirring the mixture at room temperature, 7.6 ml.(0.105 mole) of thionyl chloride is added, and the resulting mixturerefluxed overnight. The chloroform solution is then washed first with10% aqueous sodium bicarbonate solution until the wash is alkaline andthen with saturated aqueous sodium chloride solution, and the combinedwashings extracted twice with chloroform. The combined chloroform layersare then dried with sodium sulfate, filtered and the filtrate evaporatedin vacuo on a rotary evaporator to yield crude 9(p-chlorophenyl)-l,5-diazabicyclo [4.3.0]nonane, B.P. -155 C.

A solution of 2.0 g. of the free base in dry diethyl other is treatedwith hydrogen chloride gas, and the resulting solid filtered OE anddried to yield hygroscopic9-(p-chlorophenyl)-1,5-diazabicyclo-[4.3.0]nonane hydrochloride, M.P.147-l52 C.

7 EXAMPLE 3 9-phenyl-1,5-diazabicyclo [4.3.0]nonane Step A: Preparationof 2-(3-hydroxypropyl)-6-phenyl- 4,5-dihydropyridazin(2I-I) 3 one.To aflask equipped with a condenser, Dean-Stark tube and stirrer is added44.5 g. (0.25 mole) of 3-benzoylpropionic acid, 27 g. (0.3 mole) of3-hydrazinopropanol, 1 g. of p-toluenesulfonic acid and 500 ml. oftoluene. The mixture is stirred and refluxed until water ceases toseparate in the Dean- Stark tube. The solvent is then removed in vacuoon a rotary evaporater to yield an oil which solidifies on standing. Theresulting solid material is crystallized from benzene-pentane to obtain2-(3-hydroxypropyl)-6-phenyl- 4,5-dihydropyridazin(2I-I)-3-one, M.P.65-68 C.

Step B: Preparation of1-(3-hydroxypropyl)-3-phenylhexahydropyridazine.To a flask equipped witha stirrer, condenser, gas inlet tube and Soxhlet tube containing 30.0 g.(0.13 mole) of2-(3-hydroxypropyl)-6-phenyl-4,5-dihydropyridazin(2H)-3-one is addedunder nitrogen atmosphere 34.4 g. (0.9 mole) of lithium aluminum hydrideand 2000 ml. of absolute diethyl ether. The contents of the flask arestirred and refluxed for 80 hours and then cooled in an ice bath. To thecooled mixture is then added dropwise 68.8 ml. of 2 N sodium hydroxideand 103.2 ml. of water. The resulting mixture is then filtered, and thefiltrate concentrated on a rotary evaporator to obtain1-(3-hydroxypropyl)-3 phenyl-hexahydropyridazine as a viscous oil.

Step C: Preparation of 9-phenyl-1,5-diazabicyclo[4.3.0] nonane-To aflask equipped with a stirrer, condenser and dropping funnel is added18.0 g. (0.08 mole) of 1-(3-hydroxypropyl)-3-phenyl-hexahydropyridazineand 60 ml. of dry chloroform. While stirring the mixture at roomtemperature, a solution of 5.6 ml. of thionyl chloride in 16 ml. ofchloroform is added and the resulting mixture refluxed overnight. Thechloroform solution is then washed first with aqueous sodium bicarbonatesolution until the wash is alkaline and then with saturated aqueoussodium chloride solution, and the combined washings extracted twice withchloroform. The combined chloroform layers are then dried with sodiumsulfate, filtered, the filtrate evaporated in vacuo on a rotaryevaporator and the residue distilled to yield 9 phenyl-1,5-diazabicyclo-[4.3.0]nonane, B.P. 9395 C./0.7 mm.

A solution of 2.0 g. of the free base in dry diethyl ether is treatedwith hydrogen chloride gas, and the resulting solid filtered off anddried to yield hygroscopic 9-phenyl- 1,5-diazabicyclo[4.3.01nonanehydrochloride, M.P. 122- 126 C.

EXAMPLE 4 9- (p-methoxyphenyl)-5-methyl-1,5-diazacyclononane Step A:Preparation of N -methyl iodide salt of 9-(pmethoxyphenyl) 1,5diazabicyclo [4.3.0]nonane.-To a flask equipped with a stirrer, droppingfunnel and drying tube is added 24.2 g. (0.102 mole) of9-(p-methoxyphenyl)-1,5-diazabicyclo[4.3.0]nonane and 500 ml. of diethylether. The mixture is stirred, and there is added thereto dropwise 10.9ml. (0.204 mole) of methyl iodide. The resulting mixture is stirredovernight at room temperature, and the resulting solids filtered off andcrystallized from methylene chloride-diethyl ether to yield the N-methyl iodide salt of9-(p-methoxyphenyl)-1,5-diazabicyclo[4.3.0]nonane, MJP. 194-l97 C.

Step B: Preparation of 9- (p-methoxyphenyl)-5-methyl-1,5-diazacyclononane.--A flask equipped with a magnetic stirring bar,drying tube and a gas inlet tube extending to the bottom of the flask iscooled in a Dry Ice-acetone bath. About m1. of ammonia is then condensedin the flask and then 5.0 g. (0.13 mole) of N -methyl iodide salt of 9(p methoxyphenyl) 1,5 diazabicyclo[4.3.0] nonane is added to the flask.The resulting mixture is stirred and then 0.76 g. (0.033 mole) of sodiumis added in small pieces. After addition of the sodium, the cooling bathis removed and the excess ammonia allowed to evaporate overnight. Theresidue is dissolved in a mixture of chloroform and ice water. Thechloroform phase is extracted with 1 N hydrochloric acid until theaqueous extracts are acid and the acidified extracts made alkaline withsodium hydroxide pellets and then extracted with chloroform. Theresulting chloroform extract is then evaporated on a rotary evaporaterto yield 9-(p-methoxyphenyl)-5-methyl-1,5-diazacyclononane as a viscousoil. The base is dissolved in a mixture of diethyl ethermethylenechloride and the resulting solution treated with dry hydrogen chlorideto obtain 9-(p-methoxyphenyl)-5- methyl-1,5-diazacyclononanedihydrochloride. No accurate melting point of the compound isdeterminable because of its hygroscopocity.

EXAMPLE 3 9-phenyl-5-methyl-1,5-diazacyclononane N A H3 Step A:Preparation of N -methyl iodide salt of 9- phenyl 1,5diazabicyclo[4.3.0]nonane.A mixture of 5.0 g. (0.025 mole) of9-phenyl-1,S-diazabicyclo[4,3,0] nonane, 7.1 g. (0.05 mole) of methyliodide and 100 ml. of absolute diethyl ether is stirred for 20 hours atroom temperature and the resulting solids recovered by filtration toobtain the N -methyl iodide salt of9-phenyl-1,5-diazabicyclo[4.3.0]nonane, M.P. 200202 C.

Step B: Preparation of 9-phenyl-5-methyl-1,S-diazacyclononane.--A flaskequipped With a magnetic stirring bar, drying tube and gas inlet tubeextending to the bottom of the flask is cooled in a Dry Ice-acetonebath. About ml. of ammonia is then condensed in the flask and then 6.0g. (0.0174 mole) of N -methyl iodide salt of 9-phenyl-1,5-diaza'bicyclo[4.3.0]nonane is added to the flask. Theresulting mixture is stirred and then 1.0 g. (0.0435 mole) of sodium isadded in small pieces. After addition of the sodium, the cooling bath isremoved and the excess ammonia allowed to evaporate overnight. Theresidue is dissolved in a mixture of chloroform and ice Water. Thechloroform phase is extracted with 1 N hydrochloric acid until theextracts are acid and the acidified extracts made alkaline with sodiumhydroxide pellets and then EXAMPLE 69-pheny1-5-methyl-1,5-diazacyclononane Step A: Preparation of N -methyliodide salt of 9-(pchlorophenyl) 1,5 diazabicyclo [4.3.0]nonane.Amixture of 6.0 g. (0.025 mole) of9-(pchlorophenyl)-1,5-diazabicyclo[4.3.0]nonane, 7.2 g. (0.05 mole) ofmethyl iodide and 120 ml. of absolute diethyl ether is stirred for 20hours at room temperature, and the resulting solids recovered byfiltration to obtain the N -methyl iodide salt of 9 (p chlorophenyl)l,S-diazabicyclo[4.3.0]nonane, M.P. l99.-202 C.

Step B: Preparation of9-phenyl-5-methyl-1,S-diazacyclononane.-Followin-g the procedure of StepB of Example 5 and employing an additional equivalent of sodium and anequivalent amount of the N -methyl iodide salt of 9-(p chlorophenyl) 1,5diazabicyclo[4.3.0]nonane in place of the N -methyl iodide salt of9-phenyl-l,5-diazabicyclo[4.3.0]nonane used therein, there is obtained9- phenyl-5-methyl-l,5 diazacyclononane monohydrochloride.

What is claimed is:

1. A compound selected from the group consisting of diazacyclononanes ofthe formula and non-toxic pharmaceutically acceptable acid additionsalts thereof, wherein R represents hydrogen or lower alkoxy; and

R represents straight chain lower alkyl.

2. The compound of claim 1 which is9-(p-methoxyphenyl)-5-methyl-1,S-diazacylononane.

3. The compound of claim 1 which is 9-phenyl-5-methyl1,5-diazacyclononane.

4. A process for preparing a compound of claim 1 in free base form whichcomprises contacting a compound of the formula wherein R representshydrogen, chloro or lower alkoxy; R represents straight chain loweralkyl; and X represents halogen having an atomic weight of at least 35,with sodium in the presence of liquid ammonia.

References Cited UNITED STATES PATENTS 3,509,132 4/ 1970 Houlihan260-239 ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

Disclaimer 3,663,536.Wz'lliam J. Houlz'han, Mountain Lakes, NJ.1,5-DIAZACYCLO- NONANES. Patent dated. May 16, 1971. Disclaimer filed.-Aug. 12, 1971, by the assignee, Samoa-Wander, Inc. Hereby disclaims theportion of the term of the patent subsequent to Apr. 28, 1987.

[Official Gazette May 22,1973.]

